The invention relates to compounds including neurotensin, a neurotensin analog, or a neurotensin receptor agonist bound to a peptide vector and uses thereof. Neurotensin is 13 amino acid peptide possessing numerous biological activities. Injections of neurotensin in the central nervous system produce, among other effects, antipsychotic and hypothermic effects. Intravenous delivery of neurotensin, however, does not result in these effects, as the blood-brain barrier (BBB) effectively prevents peripheral neurotensin from reaching the receptors in the central nervous system (CNS) receptors.
Reduction of body temperature (hypothermia) provides one of the best forms of neuroprotection against brain damage resulting from injury (e.g., in subjects who have suffered from a nerve, brain, or spinal cord injury, or stroke). Prior to the present invention, methods for reducing body temperature have been inadequate. Physical means for reducing body temperature include the use of external methods (e.g., cooling blankets, cooling helmet, ice packs, and ice baths) as well as the use of internal methods (e.g., cooling probes, infusion of cold fluid). These techniques can be complex and expensive, and can lead to delays in the onset of hypothermia. Sustained maintenance of hypothermia may also be difficult using these methods. Finally, these methods can cause severe shivering, necessitating the need for co-medications such as paralytic agents or sedatives. Given the number of strokes (795,000), cardiac arrests of cardiac origin (325,000), severe traumatic head injuries (300,000), and open heart surgeries (694,000) each year in the United States where hypothermic treatment can be beneficial, there is a need for improved methods of inducing hypothermia.
In the development of a new therapy for brain pathologies, the BBB is considered a major obstacle for the potential use of drugs for treating disorders of the CNS. The global market for CNS drugs was $68 billion in 2006, which was roughly half that of global market for cardiovascular drugs, even though in the United States, nearly twice as many people suffer from CNS disorders as from cardiovascular diseases. The reason for this imbalance is, in part, that more than 98% of all potential CNS drugs do not cross the BBB. In addition, more than 99% of worldwide CNS drug development is devoted solely to CNS drug discovery, and less than 1% is directed to CNS drug delivery. This may explain the lack of therapeutic options available for major neurological diseases.
The brain is shielded against potentially toxic substances by the presence of two barrier systems: the BBB and the blood-cerebrospinal fluid barrier (BCSFB). The BBB is considered to be the major route for the uptake of serum ligands since its surface area is approximately 5000-fold greater than that of BCSFB. The brain endothelium, which constitutes the BBB, represents the major obstacle for the use of potential drugs against many disorders of the CNS. As a general rule, only small lipophilic molecules may pass across the BBB, i.e., from circulating systemic blood to brain. Many drugs that have a larger size or higher hydrophobicity show high efficacy in CNS targets but are not efficacious in animals as these drugs cannot effectively cross the BBB. Thus, peptide and protein therapeutics are generally excluded from transport from blood to brain, owing to the negligible permeability of the brain capillary endothelial wall to these drugs. Brain capillary endothelial cells (BCECs) are closely sealed by tight junctions, possess few fenestrae and few endocytic vesicles as compared to capillaries of other organs. BCECs are surrounded by extracellular matrix, astrocytes, pericytes, and microglial cells. The close association of endothelial cells with the astrocyte foot processes and the basement membrane of capillaries are important for the development and maintenance of the BBB properties that permit tight control of blood-brain exchange.
Thus, there exists a need for improved delivery of neurotensin to its target sites.